The 5A/6A polymorphism in the promoter of the stromelysin gene is a novel pathogenetic risk factor for AMI.

Background Endothelial lipase (EL) is a major determinant of high-density lipoprotein-cholesterol (HDL-C) metabolism and promotes monocytes recruitment. The local expression of EL could influence atherogenesis directly, in addition to its systemic role in HDL metabolism. The EL gene has a common 584C/T polymorphism, but it is unclear whether this polymorphism is associated with HDL-C levels or acute myocardial infarction (AMI). Methods and ResultsA case -control study of 107 AMI patients and 107 control subjects was conducted. T allele frequency was lower in the AMI group than in controls (0.18 vs 0.26, p<0.05). No significant association was found between the 584C/T polymorphism and HDL-C levels. Multivariate regression analyses showed that the association of the T allele with AMI was statistically significant and independent of other risk factors when age, sex, hypertension, hypercholesterolemia, and diabetes mellitus were included in the analyses (odds ratio (OR), 0.52; 95% confidence interval (95% CI) 0.28-0.98; p=0.04). However, when smoking status was included, the association of the T allele with AMI did not remain statistically significant (OR, 0.61; 95% CI 0.32-1.18; p=0.14). Conclusions The 584C/T polymorphism of the EL gene was associated with AMI independently of HDL-C levels and thus may be involved in the pathogenesis of AMI. (Circ J 2007; 71: 842 -846)

-s. Cardiomyocyte apoptosis in autoimmune cardiomyopathy: mediated via endoplasmic reticulum stress and exaggerated by norepinephrine. Am J Physiol Heart Circ Physiol 293: H1636-H1645, 2007. First published June 1, 2007; doi:10.1152 doi:10. /ajpheart.01377.2006 suggests that the autoimmune cardiomyopathy produced by a peptide corresponding to the sequence of the second extracellular loop of the ␤ 1-adrenergic receptor (␤1-ECII) is mediated via a biologically active anti-␤ 1-ECII antibody, but the mechanism linking the antibody to myocyte apoptosis and cardiac dysfunction has not been well elucidated. Since the ␤ 1-ECII autoantibody is a partial ␤1-agonist, we speculate that the cardiomyopathy is produced by the ␤ 1-receptormediated stimulation of the CaMKII-p38 MAPK-ATF6 signaling pathway and endoplasmic reticulum (ER) stress, and that excess norepinephrine (NE) exaggerates the cardiomyopathy. Rabbits were randomized to receive ␤ 1-ECII immunization, sham immunization, NE pellet, or ␤ 1-ECII immunization plus NE pellet for 6 mo. Heart function was measured by echocardiography and catheterization. Myocyte apoptosis was determined by terminal deoxytransferasemediated dUTP nick-end labeling and caspase-3 activity, whereas CaMKII, MAPK family (JNK, p38, ERK), and ER stress signals (ATF6, GRP78, CHOP, caspase-12) were measured by Western blot, immunohistochemistry, and kinase activity assay. ␤ 1-ECII immunization produced progressive LV dilation, systolic dysfunction, and myocyte apoptosis. These changes were associated with activation of GRP78 and CHOP and increased cleavage of caspase-12, as well as increased CaMKII activity, increased phosphorylation of p38 MAPK, and nucleus translocation of cleaved ATF6. NE pellet produced additive effects. In addition, KN-93 and SB 203580 abolished the induction of ER stress and cell apoptosis produced by the ␤ 1-ECII antibody in cultured neonatal cardiomyocytes. Thus ER stress occurs in autoimmune cardiomyopathy induced by ␤ 1-ECII peptide, and this is enhanced by increased NE and caused by activation of the ␤ 1-adrenergic receptor-coupled CaMKII, p38 MAPK, and ATF6 pathway.cardiomyocytes; signal transduction EVIDENCE HAS ACCUMULATED indicating that autoimmunity plays an important role in viral myocarditis and dilated cardiomyopathy (18). Among the various known anti-heart autoantibodies, an antibody activating the human ␤ 1 -adrenergic receptor (␤ 1 -AR) has been best studied. The autoantibody is not only present in 30 -40% of patients with dilated cardiomyopathy (7,20) but also has been shown to predict increased mortality in the patients (30). The importance of the ␤ 1 -AR antibody in heart failure has been established by direct demonstration of dilated cardiomyopathy in animals immunized with a peptide corresponding to the sequence of the second extracellular loop of the ␤ 1 -AR (␤ 1 -EC II ) (8, 21). In addition, the ␤ 1 -EC II antisera obtained from the experimental animals have been shown to be biologically active (28,29), with a proapoptotic action via activation of the...

ilated cardiomyopathy (DCM) is characterized by ventricular dilatation and depressed myocardial contractility, resulting in progressive refractory congestive heart failure and sudden death from ventricular arrhythmias (mainly ventricular tachycardia (VT) and subsequent ventricular fibrillation). 1 A structural increase in ventricular volume (cardiac remodeling) has been viewed as not only an adaptive consequence of initial myocardial damage, but an important determinant of the progression of heart failure. Although risk stratification of cardiac remodeling and ventricular arrhythmias in DCM is an important issue in clinical practice, the factors that lead to cardiac remodeling or induction of VT are not well defined.The adrenergic nervous system, especially through -1-adrenergic receptor ( 1-AR) activation, appears to be of major importance not only in the genesis or progression of cardiac remodeling but also in induction of VT. 2 In transgenic mice, cardiac overexpression of human 1-AR produced an overtly cardiomyopathic phenotype and ultimately chamber dilatation and systolic dysfunction. 3 Clinical evidence has accumulated of the beneficial effect of blockade of 1-AR on cardiac remodeling and prognosis in Circulation Journal Vol.66, August 2002 patients with heart failure caused by DCM or myocardial infarction. 4,5 In the CIBIS-II study, bisoprolol, a highly selective 1-AR blocker, improved the survival rate in patients with heart failure and more importantly, also showed that bisoprolol reduced sudden death most likelycaused by lethal ventricular arrhythmia and hospital admissions for malignant ventricular arrhythmia. 6 The MERIT-HF study showed that metoprolol, a selective 1-AR blocker, also reduced sudden death in patients with heart failure. 7 Accordingly, it seems reasonable to suppose that the signals mediated by 1-AR play an important role in the arrhythmogenesis of heart failure.Beta-1-AR is encoded by a gene comprising a single exon located on chromosome 10q24-26 and consists of 477 amino acids. 8 To date, 18 genetic variants of the single nucleotide chain have been identified. Although 17 of these are located at the coding region, amino acid changes occur only in 7 variants (Ser49Gly, Ala59Ser, Arg389Gly, Arg399Cys, His402Arg, Thr404Ala and Pro418Ala). 9 None of these regions other than the 389 residue have been implicated in the precise function of the 1-AR. The Arg389Gly variant is located at the interface between the last transmembrane helix and the intracellular tail, adjacent to the phosphorylation sites and thought to be critical for Gprotein coupling and subsequent cell signaling. Interestingly, functional studies using transfected fibloblasts indicated that the Arg389 1-AR had approximately 3-fold the adenylyl cyclase activity of the Gly389 1-AR when stimulated by isoproterenol. 10 Therefore, it is quite possible that the Arg389Gly polymorphism functions as either a gene for susceptibility for DCM (role in the emergence of DCM) or a modifier gene (role in the evolution/prognosis Beta-1-ad...

Cardiac norepinephrine (NE) uptake activity is reduced in congestive heart failure. Our studies in intact animals suggest that this effect on the cardiac sympathetic nerve endings is caused by oxidative stress and/or NE toxic metabolites derived from NE. In this study, we investigated the direct effects of NE on neuronal NE uptake activity and NE transporter (NET), using undifferentiated PC12 cells. Cells were incubated with NE (1-500 microM) either alone or in combination of Cu(2+) sulfate (1 microM), which promotes free radical formation by Fenton reaction for 24 h. NE uptake activity was measured using [(3)H]NE. Cell viability was determined with the use of Trypan blue exclusion and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay, and cellular oxidative stress by dichlorodihydrofluorescein fluorescence and the GSH/GSSG ratio. Cell viability was reduced by NE >100 microM. At lower doses, NE produced oxidative stress and a dose-dependent reduction of NE uptake activity without affecting cell viability significantly. Cu(2+), which has no direct effect on NE uptake activity, potentiated oxidative stress and reduction of NE uptake activity produced by NE. This decrease of NE uptake activity was associated with reductions of NE uptake binding sites and NET protein expression by using the radioligand assay and Western blot analysis, but no changes in NET gene expression. In addition, the free-radical scavenger mannitol, and antioxidant enzymes superoxide dismutase and catalase, reduced oxidative stress and attenuated the reductions of NE uptake activity and NET protein produced by NE/Cu. Thus our results support a functional role of oxidative stress in mediating the neuronal NE uptake reducing effect of NE and that this effect of NE on NET is a posttranscriptional event.